Abstract:
The artery-plugging gunk that provokes a fatal stroke or heart attack can start amassing during childhood, yet no one has known what sets off this insidious accumulation. New research suggests that the attraction between gobbets of cholesterol in the blood and particular molecules in artery walls might foment the buildup. The study reveals the earliest stages of America's number one killer and might allow doctors to pinpoint more people who are at risk for stroke or heart attack.

Epidemiological studies have linked atherosclerosis to many factors, including high blood concentrations of low-density lipoproteins (LDLs), the so-called bad form of cholesterol. Cardiovascular researchers disagree over what sparks the formation of fatty atherosclerotic lesions. Some champion inflammation of the arterial lining caused by injury or infection, an idea that's garnered a lot of popular interest. Others argue that oxidants such as hydrogen peroxide attack LDLs, making them targets for immune cells that then glom onto the arterial lining. Evidence has been accruing, however, that atherosclerosis begins when LDL particles themselves lodge in the artery lining, says Kevin Jon Williams of Thomas Jefferson University in Philadelphia, Pennsylvania. A molecule on the surface of LDL particles called apolipoprotein B, or apoB, can adhere to support molecules in the arterial wall that help the blood vessel hold its shape. According to the "response to retention" hypothesis, this t�te-�-t�te might detain LDL in the arterial wall and set off the chain of events that leads to atherosclerosis.

To test whether the attraction between these two molecules instigates fat buildup, Sk�l�n and colleagues created three types of mice, each of which carries a different form of apoB that doesn't bind to the support molecules. After allowing the rodents to gorge on a high-fat diet for 20 weeks, the researchers killed the animals and measured the extent of fatty buildup plastering the lining of the aorta, the large vessel leading from the heart. In the three groups with altered apoB, the area covered by the lesions was less than half that in the control group, which sported normal apoB. Although the findings do not rule out a role for inflammation and oxidation, they argue that LDL attachment comes first, says cell biologist Jan Bor�n of G�teborg University in Sweden, who led the research team: "The vicious cycle [of atherosclerosis] could start here."

The study "is the first direct proof of this hypothesis," says atherosclerosis expert Ira Tabas of Columbia University in New York City. Genetic differences in apoB among people might explain why some patients have what seem like perilously high LDL concentrations but don't develop atherosclerosis, whereas others with normal concentrations die from heart attacks. Testing for apoB variants might allow early identification of people likely to develop atherosclerosis. Researchers might also develop drugs that keep apoB from gluing LDL to arteries. Williams also lauds the work, saying that the findings should remind everyone that, contrary to the popular thinking that links inflammation with atherosclerosis, controlling LDL levels is the key to thwarting cardiovascular disease. So put down that doughnut and get off the couch.